Abstract

Background Few follow-up studies of depression have evaluated
depressive symptomatology over time at both threshold and sub-threshold
levels.

Aims To evaluate long-term longitudinal symptomatic course after an
episode of severe depression.

Method A total of 61 participants from a previous study cohort
underwent a detailed interview covering the longitudinal course of depression
and pharmacological treatment over 8–11 years of follow-up.

Results Of the follow-up months, 52% were spent at an asymptomatic
level, 15% at minor symptom level, 20% at residual symptom level and 13% at
full depression level. Also, 30% of follow-up months were spent in an episode
of depression, and 18% of patients never achieved asymptomatic status during
follow-up. The percentage of patients at each symptom level remained
relatively stable after the first 2 years, but levels in individuals
fluctuated, with a mean of two changes in symptom levels per follow-up
year.

Conclusions After severe episodes, sub-syndromal levels of
depression are common and persistent, with considerable fluctuation suggesting
a continuum between sub-syndromal subtypes and full depression.

Unipolar depression in the past has been considered as an episodic illness,
usually following a relapsing–remitting course, but in a minority of
cases becoming a chronic refractory illness. However, more recent studies have
identified lower-grade depressive subtypes such as dysthymic disorder
(
Akiskal, 1983), recurrent
brief depression (
Angst et al,
1990), minor depressive disorder
(
Skodol et al, 1994)
and sub-syndromal symptomatic depression
(
Judd et al, 1994).
Rather than being entirely separate disorders these may be part of the same
spectrum of illness as full depression, in a continuum in which sufferers
fluctuate between related subtypes at different times in the course of the
illness (
Judd et al,
1997). With few exceptions, published long-term follow-up studies
of depression to date have concentrated on recovery and recurrence rates and
state at outcome assessment, rather than evaluating inter-episodic depressive
symptoms, sub-syndromal depression or symptom change over time. We followed up
a cohort of people with severe depression, originally recruited in the early
1990s (
Paykel et al,
1995;
Ramana et al,
1995), using a longitudinal interview that allowed measurement of
minor or sub-threshold forms of illness in addition to symptom change and
inter-episodic symptomatology. Previously we have reported recurrence rates
(
Kennedy et al,
2003). In this paper we report symptom levels below major
disorder, and time spent at various symptom levels.

METHOD

Subjects and tracing

The sample, tracing and interview methods have been reported in detail
previously (
Kennedy et al,
2003). Seventy consecutive subjects, predominantly psychiatric
inpatients with severe depression who satisfied the Research Diagnostic
Criteria (
Spitzer et al,
1978) for definite primary unipolar major depression, were
recruited from treatment facilities between 1990 and 1992
(
Ramana et al, 1995).
Subjects with a concurrent major psychiatric or physical illness were
excluded. Subjects originally underwent 3-monthly interviews until remission
and for up to 15 months thereafter to ascertain relapse, residual symptoms and
impact of life events, social support, marital relationships and expressed
emotion on outcome (Paykel et al,
1995,
1996;
Ramana et al, 1995;
Hayhurst et al,
1997). Both the original and present studies were approved by
local Research Ethical Committees. For the current follow-up subjects were
traced, through local records and by the local health authority or the
National Health Service Register at the Office for National Statistics, to
current general practitioners or psychiatrists, and approached through them
for interview.

Interviews and information obtained

Participants were interviewed 8–11 years after initial recruitment,
by an experienced psychiatrist (N.K.) masked to original study data, after
written permission had been obtained. Prior to interview, psychiatric and/or
general practice case notes were examined over the full follow-up period to
obtain as much information as possible regarding number, length and treatment
of depressive episodes in addition to any depressive symptoms recorded.

Data were collected at one or two semi-structured interviews, lasting
3–5 h each, which evaluated longitudinal clinical and treatment
information over the entire follow-up period.

Longitudinal clinical and treatment information

Longitudinal symptom and treatment information over the follow-up period
was obtained using an adaptation of the Longitudinal Interview Follow-up
Evaluation (LIFE;
Keller et al,
1987), originally developed for the National Institute of Mental
Health Collaborative Depression Study (NIMH CDS). The LIFE was originally
designed for shorter follow-up periods, to describe psychopathology in a
continuous way and to record accurately subcriteria symptoms between illness
episodes. This interview was used retrospectively over the entire follow-up
period in this study. It is operationally linked to the Research Diagnostic
Criteria and has been adapted to satisfy DSM–IV
(
American Psychiatric Association,
1994) criteria. Using time-anchoring cues specific for each
subject, each year of follow-up in turn was examined in detail for evidence of
depressive symptoms. Onset and offset of symptoms of depression were dated to
within a month, and charts, each covering a period of 1 year, were completed.
Monthly psychiatric status ratings (PSRs), based on DSM–IV symptoms of
depression, were recorded to identify change over time in depressive symptoms
and total time spent at various symptom levels for each subject. Criteria are
shown in
Table 1. An additional
point above full criteria for depression was added compared with the original
LIFE to allow fuller evaluation of severity within major depression, so that
in this study PSRs were rated 1–7 rather than the original 1–6. To
aid recall, use was made of psychiatric and/or general practice notes to
identify episodes of depression and treatment prior to longitudinal interview.
Family members or partners, where available, were interviewed to obtain
further information. Final assignment of monthly PSRs was made after further
assessment of all available information during that follow-up month.

For analysis of time spent at each symptom level during follow-up, PSRs
were further subdivided into four symptom severity levels adapted from the
LIFE (Keller et al1987,
1992). The PSRs 7–5
fulfilled criteria for major depressive disorder, PSRs 4 and 3 for residual
symptoms of depression, PSR 2 for minor symptoms and PSR 1 for no symptoms.
The LIFE definition of recovery of at least two consecutive months at PSR 2 or
1 was used in this study.

Statistical methods

Statistical analyses were carried out using the Statistical Package for the
Social Sciences, version 10.0 for Windows
(
SPSS, 1999). Validity of
using the adapted LIFE over the longer follow-up period of this study was
evaluated using the methods of Bland & Altman
(
1986). First, χ
2 tests compared grouped Hamilton Rating Scale for Depression
(HRSD;
Hamilton, 1960) scores
at 3-monthly intervals with grouped LIFE scores at overlapping time points.
The HRSD scores were grouped into asymptomatic (<7), residual symptoms
(8–16) and major depression (≥17), and LIFE PSRs were similarly
grouped into asymptomatic (1–2), residual symptoms (3–4) and major
depression (5–7). Raw LIFE scores were then compared with raw HRSD and
Clinical Interview for Depression (CID;
Paykel, 1985) scores at
overlapping time points using scatterplots and the Pearson correlation
coefficient (r).

Primary analysis variables were percentages of follow-up time spent at the
four levels of symptom severity and changes in symptom severity levels per
patient per year. Subjects in their first lifetime episode at initial
presentation and subjects with previous episodes of DSM–III–R
(
American Psychiatric Association,
1987) depression were compared using χ2 or
Fisher’s exact test for categorical variables, and Student’s
t-test for continuous variables or the Mann–Whitney
U-test where distribution was non-normal. Bivariate and multivariate
logistic regression models were used to assess which index variables predicted
a longer time spent at sub-threshold and full depression during follow-up. All
61 subjects interviewed using the adapted LIFE had full data-sets.

RESULTS

Tracing and sample characteristics

Full details of tracing and sample characteristics are given elsewhere
(
Kennedy et al,
2003). A total of 61 (92%) of the 66 living members of the
original study cohort underwent full longitudinal interview and case-note
review. Four subjects died early in follow-up, two from suicide and two from
natural causes. In five cases the subjects or their general
practitioner/psychiatrist refused a follow-up interview. The follow-up period
covered a mean of 113 months (s.d.=8, range 97–128) during which full
monthly clinical and treatment ratings were assessed.

The majority of subjects were female (67%) and married or in a stable
cohabitation (75%). Mean age at intake was 40 years (s.d.=12, range
20–63) and mean age of first depression was 33 years (s.d.=14, range
9–57). At intake, diagnoses were mainly DSM–III–R recurrent
depression (67%) and DSM–III–R moderate or severe depression
(75%). Almost one-fifth (16%) had a history of DSM–III–R dysthymia
in addition to major depression, with 7% having a chronic episode of at least
2 years’ duration at index interview. Subjects whose index episode was
their first showed no differences in index variables from those with previous
episodes, except for older mean age of first depression: mean 38 (s.d.=10)
years v. mean 29 (s.d.=12) years; t=2.5, d.f.=59,
P<0.05.

Validity of adapted LIFE interview

Adapted LIFE was validated in this longer-term follow-up study by comparing
LIFE scores at overlapping time points with HRSD and CID scores rated
prospectively at approximately 3-monthly intervals for the first 18 months of
the shorter-term follow-up study (
Ramana
et al, 1995). The interviewer in the current study (N.K.)
was masked to HRSD and CID scores from the original shorter-term study until
full analysis was complete. When grouped HRSD and LIFE PSRs were compared by
cross-tabulation, relationships between the grouped scores were highly
significant (P<0.001 by χ2 test) at each
overlapping time point. Scatterplots of raw scores showed a linear association
between the variables at each time point, and strong correlations between raw
LIFE scores and both HRSD (r=0.75–0.90) and CID scores
(r=0.78–0.88) at overlapping time points were found, suggesting
that the adapted LIFE scale had good validity over the most distal period and
that of most rapid symptomatic change.

Depressive symptom severity and change over follow-up

During a total of 6907 patient-months rated over follow-up, subjects spent
52.0% of follow-up months at an asymptomatic level (PSR 1), 15.2% at minor
symptom level (PSR 2), 19.6% at residual symptom level (PSR 3–4) and
13.2% at full depression level (PSR 5–7)
(
Table 2). Subjects spent 30%
of follow-up months in an episode of depression using the LIFE definition of
recovery (two consecutive months at PSR 1–2). Subjects with no prior
episode of depression spent significantly less time in a major depressive
state over follow-up and showed a trend towards having a higher percentage of
asymptomatic months.

Figure 1 shows the
percentage of subjects at different symptom levels for each month of follow-up
to 12 months and
Figure 2 shows
the percentage at 6-monthly intervals to 102 follow-up months. The percentage
with full depression fell dramatically over the first year of follow-up and
the residual symptom percentage increased, followed by an increase in
percentages at other symptom levels. Over the rest of the follow-up the
percentage of subjects at various symptom levels remained stable, with more
subjects having a rating of residual depression rather than major
depression.

During the first year of follow-up the subjects spent 25% of follow-up
months at an asymptomatic level, 15% at minor symptom level, 30% at residual
symptom level and 30% at full depression level. During the second year,
asymptomatic months had risen to 50% and minor symptom months to 17%, whereas
months at residual symptom level had decreased to 19% and months at full
depression to 14%. For each year of follow-up after the second year, symptom
levels showed little change: 52–61% of follow-up months were rated at an
asymptomatic level, 14–19% at a minor symptom level, 16–22% at a
residual symptom level and 8–13% with full depression. A total of 58
(95%) of 61 subjects recovered (two consecutive months at PSR 1–2) from
the index episode during follow-up. However, 11 subjects (18%) never achieved
full asymptomatic status (PSR 1) for even a month during follow-up.

Change in depressive symptom severity levels

Table 3 shows the extent to
which subjects changed symptom levels during follow-up. Over 70% of the
subjects spent time at each of the four levels of symptom severity, with the
majority of the rest spending months at three levels. There was a mean of
almost two changes in symptom levels per subject every year. Subjects in the
first episode subgroup showed a trend towards fewer changes per year than
those with previous episodes.

Antidepressant treatment during follow-up

Antidepressants were prescribed for a mean of 59.2% (s.d.=36.9) of
follow-up months. For the whole sample, the composite antidepressant score per
prescribed month, which is a measure of the adequacy of the antidepressant
dose prescribed, was relatively high: mean 2.9 (s.d.=0.9). The first-episode
subgroup was prescribed antidepressants for significantly significantly fewer
percentage months during follow-up: mean 45% (s.d.=41%) v. mean 66%
(s.d.=33%); t=2.2, d.f. 59, P<0.05. However, the mean
composite antidepressant score per prescribed month was similar in the two
groups: mean 2.7 (s.d.=1.0) v. mean 2.1 (s.d.=1.3); t=1.3,
d.f.=59, P=0.21. Women were prescribed antidepressants during
significantly more percentage follow-up months than men: mean 65 (s.d.=36)
v. mean 46 (s.d.=37); d.f.=59, P<0.05. However, there was
no significant difference by gender in the mean composite antidepressant score
per prescribed month.

Predictors of time spent at full and residual depression over
follow-up

Two dependent variables were used in separate logistic regression
predictive analyses: percentage follow-up time spent at full criteria for
depression (PSR 7–5) and percentage follow-up spent at residual symptom
level (PSR 4–3) during follow-up, split at median length. A limited
number of dichotomised predictive variables were examined covering age at
index interview and at first depression (both split at mean),
socio-demographic variables, family history of affective disorder, personal
history, DSM–III–R premorbid personality disorder, illness
history, diagnostic subtypes and initial symptom severity.

As shown in
Table 4,
significant predictors of longer time at full depression after bivariate
logistic regression were female gender, greater index severity, greater index
anxiety and DSM–III–R episodes of depression prior to index
episode. The only significant predictor of a longer time spent at residual
symptom level was female gender.

Significant and near-significant predictors in bivariate logistic
regression of longer time spent at full depression and residual depression
during follow-up (n=61)

Significant or near-significant variables after bivariate analysis were
entered into multivariate logistic regressions with age at index episode
(continuous), occupational category at index and index marital status using
the same dependent variables. Only gender (odds ratio=4.63,
P<0.05) remained significant using time spent at full depression,
and none of the variables remained significant using time spent at residual
symptom level as the dependent variable.

DISCUSSION

Older long-term studies of severe depression have described clinical
outcome in terms of recovery, recurrence, chronicity and mortality. However,
longitudinal interviewing allowed a more detailed description of the time
spent at full and sub-threshold levels of depression and changing episode
status. To our knowledge, the NIMH CDS has been the only study to describe
systematically the longitudinal symptomatology of severe depression at
threshold and sub-threshold levels in the long term
(
Judd et al, 1998).
The current study therefore described, for the first time in a British sample,
longitudinal depressive symptomatology after an episode of severe long-term
depression, and evaluated whether high sustained levels of symptoms described
in the NIMH CDS were also observed in this sample.

Many patients in this sample continued to suffer from depressive symptoms,
particularly at sub-syndromal levels. After a decrease in the first 2 years
the percentage experiencing these symptoms did not attenuate further over the
next 8 years. Individual symptom levels changed frequently and the majority of
patients spent time at each different symptom level over the follow-up period.
Female gender predicted the chronicity of symptoms and a longer time spent at
full criteria for depression, despite receiving antidepressants during
significantly more follow-up months. Index severity and previous episodes
weakly predicted a longer time at full depression.

Methodological strengths and weaknesses

The strengths of the study included the high follow-up rate, interviews
being conducted by one psychiatrist to aid reliability, independently
collected index predictor data, extensive use of collateral information and
longitudinal interviewing.

Limitations included the length of follow-up time covered by the
longitudinal interview. The LIFE was originally designed to be used repeatedly
over shorter periods but has been adapted for longer-term studies
(
Surtees & Barkley, 1994).
However, the validity of using the LIFE over the entire follow-up period could
still be questioned. With this in mind, full use was made of case notes and
general practitioner records to aid in the identification of depressive
episodes prior to interview. Additionally, LIFE ratings correlated well with
prospective HRSD and CID scores collected independently for the shorter-term
study over the period of greatest symptom change and the period most distal
from follow-up interview, when unreliability might be expected to be highest,
helping to validate the adapted LIFE. Nevertheless, distinction between
sub-syndromal symptoms, such as residual and minor symptoms of depression,
particularly early in follow-up, could still have been subject to recall
bias.

The participants also were at different stages in the course of illness,
leading to difficulty in interpreting outcomes for individuals at a specific
point in their illness. However, this sample had similar entry characteristics
to previous long-term outcome studies, allowing valid comparison, and being a
clinical sample it bore considerable similarity to patients seen in general
psychiatric practice. Additionally, the sample followed up was relatively
small, limiting the power to detect weaker predictors of chronicity.

Time spent at different symptom levels and symptom change

Participants had depressive symptoms during almost half of the follow-up
months and spent 30% of follow-up time in an episode of depression despite
receiving relatively high levels of antidepressant treatment; 20% of follow-up
months were spent at a residual symptom level, in contrast to only 13% of
follow-up months at full criteria for depression. Almost one in five never
reached full asymptomatic status during follow-up. Judd et al
(
1998) in the NIMH CDS
reported similar findings over almost 9 years, with subjects receiving similar
levels of antidepressant treatment over follow-up, but they were asymptomatic
for only 40% of follow-up weeks, in contrast to 50% of follow-up months in
this study, possibly because a much higher percentage of patients with a
history of dysthymia were included.

Previous long-term studies of depression have shown high rates of
chronicity and recurrence (
Lee &
Murray, 1988;
Surtees &
Barkley, 1994). This study, with others
(
Angst & Merikangas, 1997;
Judd et al, 1998),
adds an element of lower-grade symptomatology that persists over time.
Importantly, after initial improvement from index depression, the proportion
of patients with symptoms at each level did not attenuate even after 10
follow-up years. The sustained levels of sub-syndromal symptoms in the sample
are in keeping with reports from the NIMH cohort
(
Keller et al, 1992)
that many patients eventually develop chronic lower-grade symptoms more like
dysthymia.

Sub-threshold and residual depressive symptoms after an episode of
depression are important clinically because they have been associated with
severe impairment of social functioning in most domains, and a gradient in
degree of impairment is found when comparing asymptomatic individuals with
those having sub-threshold and major depression
(
Judd et al,
2000a). Sub-threshold symptoms after an episode of
depression have also been shown to lead to early recurrence
(
Paykel et al, 1995)
and impaired long-term functioning (
Judd
et al, 2000b).

Are depressive subtypes linked on a continuum?

Milder subtypes of depression have been described, including minor
depressive disorder (
Skodol et
al, 1994), dysthymic disorder
(
Akiskal, 1983) and
sub-syndromal symptomatic depression (
Judd
et al, 1994), raising the question as to whether these
forms are separate entities or whether different clinical symptoms and
subtypes of depression are seen in individuals over time. High rates of
symptom change per subject were seen in this study. Overall percentage at each
level remained stable over time, but individual levels of symptom stability
were low. High rates of symptom change were also reported in the NIMH CDS
(
Judd et al, 1998)
and the NIMH Epidemiologic Catchment Area study when patients were
re-interviewed after 1 year (
Judd et
al, 1997). Other studies using polysomnographic and family
history data (
Akiskal et al,
1997), clinical characteristics
(
Kessler et al, 1997)
and social impairment (
Judd et
al, 2000a) have shown resemblances between
sub-threshold forms of depression and major depression. This study adds to a
growing body of research that various depressive subtypes are linked on a
continuum and that many patients will fulfil criteria for a number of these
subtypes during the course of their illness.

Predictors of chronicity

Female gender predicted more time spent at full depressive criteria and
greater chronicity of sub-threshold symptoms over time. In a long-term
follow-up of the NIMH CDS cohort, female gender was strongly associated with
recurrence (
Mueller et al,
1999). Female gender has also been associated with chronicity
(
Scott, 1988) and poor
prognosis (
Kornstein et al,
2000), although not in all studies
(
Simpson et al,
1997).

Subjects without a previous history of depression at entry had a later age
of onset of depression, spent less time at full criteria for depression and
received less antidepressant treatment during follow-up than those with
previous episodes. Judd et al
(
1998) reported similar
findings. Previous episodes of depression have consistently predicted early
relapse (
Keller et al,
1982), in addition to recurrence or poor outcome in long-term
follow-up studies (
Lee & Murray,
1988;
Mueller et al,
1999).

This follow-up study showed that symptoms at sub-syndromal levels were
common and persisted for many years after an episode of severe depression,
even with reasonable levels of antidepressant treatment. Previous long-term
studies of depression, which have concentrated on recurrence and chronicity at
full criteria, may have underestimated the impact of milder symptoms on
long-term outcome. Future treatment and outcome studies of depression also
need to focus closely on sub-syndromal disorder.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

Sub-syndromal levels of depression are common and persistent after an
episode of severe depression.

Depressive subtypes may be linked on a continuum and many patients may
fulfil criteria for various subtypes of depression during the course of their
illness.

Female gender appears to be associated with chronicity of depressive
symptoms.

LIMITATIONS

Assessment was retrospective, but longitudinal interview showed good
validity when compared with independent prospective depression scores.

Sample size was relatively small, reducing the power to detect significant
associations.

The severe, recurrent nature of depression in this sample may not be
representative of depressive illness in the general population.

Acknowledgments

This study was supported by a grant to N.K. from the University of
Cambridge, Department of Psychiatry. Carolyn Crane provided major assistance
in tracing subjects. Dr Rajini Ramana and Dr Hazel Hayhurst aided greatly in
project design. The original project was supported by a Medical Research
Council grant to Dr Zafra Cooper and E.S.P. We are grateful to the study
participants, and to the psychiatrists and general practitioners for
permission to contact their patients and to access case notes.